More than 50% of the patients with pancreatic cancer are diagnosed at the metastatic stage, which is doomed with a poor outcome and limited treatment options. The demonstrated a survival advantage of two weeks, which subsequently led to FDA approval of this agent for the treatment of advanced pancreatic cancer. However, due to the small overall survival benefit, high cost, and increased risk of toxicity, the use of erlotinib in unselected pancreatic cancer is limited. Establishing predictive biomarkers that allow better selection of patients who will most likely benefit from the addition of erlotinib to the treatment of pancreatic cancer is in urgent need. KRAS mutation status represents a proven predictive biomarker for the benefit of anti-epidermal growth factor receptor (EGFR) therapy, such as erlotinib, in metastatic colorectal cancer and non-small cell lung cancer. KRAS mutation is seen in approximately 75% of pancreatic cancer patients. However, determination of the mutational status for pancreatic cancers is infrequent due to the difficulties in accessing the pancreas. The recently developed technology in mutation detection in circulating cell-free DNA (cfDNA) provides a quantitative measure of tumor mutational load and may serve as a surrogate predictive biomarker for tumor response. Preliminary data utilizing small pancreatic tumor datasets or cfDNA samples has suggested the predictive nature of KRAS for anti-EGFR therapy within pancreatic cancer patients, but the results are inconclusive due to the small sample size. In a pilot study, we have demonstrated the feasibility of using plasma cfDNA for KRAS mutation detection in patients with pancreatic cancer. Furthermore, we have gained access to the biospecimen collected by the only phase III study on erlotinib in pancreatic cancer with biospecimen collection. In the current project, we will examine the KRAS mutation status in plasma cfDNA of 378 patients enrolled in the PA.3 study using digital PCR method and demonstrate whether KRAS mutation status will represent a predictive biomarker for the anti-EGFR inhibitor erlotinib in metastatic pancreatic cancer. Findings of this study will demonstrate 1) the utility of using plasma cfDNA as a means to determine the KRAS mutational status of a patient with pancreatic cancer and 2) the predictive value of KRAS mutation status in patient response to anti-EGFR therapy in pancreatic cancer. Such information will enable and empower future molecularly directed patient selection for personalized cancer treatment.